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GLP-1 predicts cardiovascular mortality irrespective of baseline diabetes or obesity

https://doi.org/10.1007/s00392-025-02625-4

Martin Reugels (Aachen)1, B. Kurt (Aachen)1, M. Kleber (Mannheim)2, A. G. Antwerpen (Aachen)1, K. Rex (Aachen)1, K. L. Aygar (Aachen)1, J. Bornemann (Aachen)1, N. Ganesh (Aachen)1, A. Giacin (Aachen)1, S. Just (Aachen)1, A. Kapoor (Aachen)1, A. M. Mertens (Aachen)1, K. Müser (Aachen)1, M. Neuhaus (Aachen)1, L. B. Quintana Selek (Aachen)1, R. Salagundi (Aachen)1, M. Sausen (Aachen)1, N. Tabaza (Aachen)1, J. Spießhöfer (Aachen)3, W. März (Mannheim)4, N. Marx (Aachen)1, M. Lehrke (Traunstein)5, F. Kahles (Aachen)1

1Uniklinik RWTH Aachen Med. Klinik I - Kardiologie, Angiologie und Internistische Intensivmedizin Aachen, Deutschland; 2Universitätsklinikum Mannheim Med V. - Nephrologie, Endokrinologie und Rheumatologie Mannheim, Deutschland; 3Uniklinik RWTH Aachen Med. Klinik V - Klinik für Pneumologie und Internistische Intensivmedizin Aachen, Deutschland; 4SYNLAB Holding Deutschland GmbH SYNLAB Akademie Mannheim, Deutschland; 5Klinikum Traunstein Kardiologie Traunstein, Deutschland

 

Background: Recent clinical trials showed that GLP-1 receptor agonists (GLP-1RA) improve cardiovascular outcomes in patients with diabetes or obesity and atherosclerotic cardiovascular disease (ASCVD). GLP-1RA exert various pleiotropic effects including blood glucose control, weight loss and reduction of inflammation. However, the exact underlying mechanism of how GLP-1RA improve cardiovascular outcomes is still not completely understood. Here we seek to investigate if circulating GLP-1 levels predict CV outcomes and if this association depends on baseline diabetes or obesity.

 

Methods: We measured circulating GLP-1 levels in 2326 patients with established ASCVD who underwent coronary angiography at baseline (1997-2000) and are part of the Ludwigshafen Risk and Cardiovascular Health Study. The primary endpoint of our study was cardiovascular mortality.

 

Results: Circulating GLP-1 levels were independently associated with cardiovascular mortality in patients with ASCVD (multivariable cox regression model adjusted for age, sex, diabetes, smoking, hypertension, previous cardiovascular disease, eGFR CKD-EPI, hsCRP, LDL cholesterol, hs-TroponinT and NT-proBNP: Chi2: 421.07, p=0.003). GLP-1 provided higher influence on outcome prediction compared to other cardiovascular risk predictors like sex, hs-TroponinT, LDL cholesterol, hsCRP and eGFR CKD-EPI in a variable’s importance analysis. Furthermore, GLP-1 improved model performance of the SMART risk score (a european guideline recommended tool for 10-year cardiovascular risk assessment in patients with clinical manifest ASCVD; delta Chi2: 12.29, fraction of new information: 4.2%). Interestingly GLP-1 levels were associated with cardiovascular mortality irrespective of baseline diabetes (43.1%) or obesity (23.7%; defined as BMI ≥ 30 kg/m²) (respective p-values of interaction: non-significant). Predictive capacity of GLP-1 for cardiovascular mortality was even more pronounced in the absence of baseline diabetes or obesity (no diabetes: multivariable model: Chi2: 172.81, p=0.002; Added value SMART score: delta Chi2: 16.55, fraction of new information: 12.9%; no obesity: multivariable model: Chi2: 348.23, p=0.007; Added value SMART score: delta Chi2: 9.09, fraction of new information: 3.9%).

 

Conclusion: GLP-1 is a strong and independent biomarker for cardiovascular mortality in patients with ASCVD irrespective of baseline diabetes or obesity. These data suggest a possible direct interaction between GLP-1 and cardiovascular disease beyond glucose metabolism and body composition.

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